A putative susceptibility locus on chromosome 18 is not a major contributor to human selective IgA deficiency: Evidence from meiotic mapping of 83 multiple-case families

Previous reports of an association between constitutional chromosome 18 abn ormalities and low levels of IgA suggested that this chromosome contains a susceptibility locus for selective IgA deficiency (IgAD), the most frequent Ig deficiency in humans. IgAD is genetically related to common variable im munodeficiency (CVID), characterized by a lack of additional isotypes. Our previous linkage analysis of 83 multiple-case IgAD/CVID families containing 449 informative pedigree members showed a significantly increased allele s haring in the chromosome region 6p21 consistent with allelic associations i n family-based and case-control studies and provided the evidence for a pre disposing locus, termed IGAD1, in the proximal part of the MHC. We have typ ed the same family material at 17 chromosome 18 marker loci with the averag e intermarker distance of 7 cM, A total of 7633 genotypes were analyzed in a nonparametric linkage analysis, but none of the marker loci exhibited a s ignificantly increased allele sharing in affected family members. In additi on, reverse painting and deletion mapping of a panel of constitutional chro mosome 18 deletions/translocations showed the presence of IgA-deficient and IgA-proficient patients with the same abnormality and did not reveal a reg ion commonly deleted. The linkage analysis of chromosome 8 and 21 regions i nvolved in reciprocal translocations t(8;18) and t(18;21), which were ident ified in two patients lacking IgA, did not disclose a significant allele sh aring, Although these results do not exclude the presence of a minor predis posing locus on this chromosome, such a putative locus would confer a popul ation risk of developing IgAD/CVID much lower than IGAD1.